The long term objective of this proposal is to better understand the cause of the dopaminergic cell loss in Parkinson's disease (PD). Based on a number of findings, alpha-synuclein (a-syn) has been implicated in the pathogenesis of PD as an important player in cell viability; a-Syn's effects may result from an impact on the ERK survival cascade. The specific aims of this research project are to (1) further understand the increase in active ERK for survival after 6-OHDA induced toxicity and (2) determine the downstream consequences of ERK activation and the impact of a-syn on these effects. The overall hypothesis is that the ERK pathway is activated after 6-OHDA as a compensatory mechanism and a-syn increases viability after a toxic insult by promoting the activation of ERK. A dopaminergic cell line, MN9D cells, either untransfected, or transfected with vector only, wild type or mutant a-syn, will be used to evaluate this hypothesis. In brief, the cells will be treated with 6-OHDA to elicit cell death. The involvement of ERK and a-syn in cell survival after this toxic insult will be examined via viability assays, immunoblot analysis, immunocytochemistry, immunoprecipitations, and enzyme activity assays. Since a-syn may affect the cell death in dopaminergic neurons as seen in PD, further insight into the mechanism of a-syn's actions will facilitate the development of potential therapies for PD.